Acquired damage to the brain, due to illness or injury, is a leading cause of death and disability in the United States. Yet, there are few treatments for the prevention of brain damage and neuronal death once the initial insults have occurred. It is well recognized that brain tissue becomes abnormally acidic during many conditions that cause brain damage, including stroke, inflammation, seizures, traumatic brain injury (head trauma), and infection. Recent work indicates that agents targeting the Acid-Sensing Ion Channel 1a (ASIC1a) can prevent neuronal death in mouse models of brain ischemia and stroke. My laboratory is interested in understanding how ASIC1a contributes to acidosis-induced neuronal damage. Recently, we discovered that dynorphins prevent ASIC1a desensitization. These peptides are abundant and modulate ASIC1a activity at physiological or pathophysiological concentrations. In this proposal, we will (1) determine how dynorphins modulate ASIC1a activity, (2) test strategies to limit this interaction and (3) determine the effect of dynorphin modulation on acidosis-induced neuronal death. Our preliminary data indicate that the response of human ASIC1a is different from mouse ASIC1a. We will use a transgenic mouse line that expresses human ASIC1a exclusively to determine how neuronal death and dynorphin modulation are different in neurons expressing human ASIC1a. To accomplish these goals we will use electrophysiology to analyze ASIC1a activity and cell biology methods to assess neuronal death. These findings will provide fundamental insight into ASIC1a-induced neuronal mortality. Because extracellular acidosis occurs during many types of injuries to the central nervous system these findings may impact our understanding of neuronal death in multiple injury paradigms. The Public Health Relevance: The acidosis that accompanies stroke and ischemia causes neuronal death, in large-part, by activating the acid-sensing ion channel 1a (ASIC1a). The proposed studies will analyze neuropeptide modulation of ASIC1a and determine how modulation affects characteristics central to ASIC activation and acidosis- induced neuronal death. ASIC1a represents an exciting new target for therapeutics to prevent brain injury and these studies will provide vital information to understand the fundamental mechanism of ASIC1a-induced neuronal death.